Clinician's Guide to Pulmonary Arterial Hypertension - Pocketbook

8/8/2019 Clinician's Guide to Pulmonary Arterial Hypertension - Pocketbook

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A Clinician's Guide to

Pulmonary

ArterialHypertensionSimon Stewart

Geoff Strange

Second Edition


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A Clinicians Guide toPulmonary Arterial

Hypertension


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2007 Informa UK Ltd

First published in the United Kingdom in 2007 by Informa Healthcare, Telephone House, 6977 Paul St, London

EC2A 4LQ. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street,

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Contents

Preface vii

1. Introduction 1

2. Disease background and epidemiology of

pulmonary arterial hypertension 5

3. Pulmonary arterial hypertension increasing our

understanding of disease pathophysiology 13

4. Pulmonary arterial hypertension clinical

profile and diagnosis 21

5. Improving outcomes in pulmonary arterial

hypertension pharmacological and surgical

treatment strategies 29

6. Screening and management of pulmonary

arterial hypertension 41

APPENDIX

Informative websites: pulmonary arterial hypertension 47

References 49

Index 59


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Preface

Pulmonary arterial hypertension, an uncommon but all too frequently fatal

condition, represents one of those niche areas of medicine that attracts a

small but fanatical following of experts. Such fanaticism is matched by the

pharmaceutical companies who are able to leverage enormous profits from

the successful treatment from a relatively small number of treated patients.

It would be easy to become cynical about the symbiotic relationship

between the experts and industry in pulmonary arterial hypertension but for

one thing improved awareness and treatment, leading to better health out-

comes for those unfortunate (predominantly young women) to be affected.

As an outsider who dabbled on the edges of pulmonary arterial hypertension,

I have been more than fortunate to meet and talk to many of the experts who

have put pulmonary arterial hypertension on the map and pioneered the signifi-

cant therapeutic strides outlined in this book and its first incarnation (Simon

Stewart, Pulmonary Arterial Hypertension: A Pocketbook Guide (2005), Taylor

& Francis, London & New York). In publishing this new improved version of

the book, I have been able to correct one important injustice done to one of the

hidden experts in pulmonary arterial hypertension my co-author Geoff

Strange. Suffering from his links to the pharmaceutical industry, Geoff wasunwilling to come on board as a co-author of the first book; even though he

richly deserved this position given his expert and impartial contribution. Thanks

to the success of the first book, I'm delighted that we now have the opportunity

to publish a second book that recognizes his expertise and co-authorship!

My aim in initiating and (co-)writing these two books was very simple: to

introduce the wider health community to the importance of detecting poten-

tially hidden pulmonary arterial hypertension and sending those unfortunateto be affected into the fanatical and passionate care routinely offered by

expert centres. It is only through a united effort between the wider health

community and the experts that we can positively alter the still fatal natural

history of pulmonary arterial hypertension.


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I hope this book achieves its aim and provides you with a succinct and

invaluable overview of pulmonary arterial hypertension. Perhaps, one day, it

will prompt you to suspect the presence of pulmonary arterial hypertension

and save the life of an individual who would die prematurely without expert

care and treatment.

Simon Stewart

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A relatively rare but devastating diseasePulmonary arterial hypertension (PAH) is a relatively rare but potentially

life-threatening disease. PAH is a particularly sinister condition that is, inmost forms, likely to be diagnosed late and is associated with progressive

clinical deterioration and premature death.13

The underlying processes that lead to the development of PAH are complex

and the disease remains clinically silent until the right side of the heart

begins to fail, initially only on exertion, but in later stages of the disease, at

rest. Definitive diagnosis requires specialist skills. Invasive diagnostic proce-

dures are necessary to determine the underlying aetiology and associateddisease states. Due to the non-specific nature of the early symptom manifes-

tations, diagnosis is typically not confirmed until up to 3 years from

the initial symptom presentation, when disease pathophysiology is well

developed.13

In recent years there has been increasing interest in the causes, conse-

quences, and treatment of PAH. Pulmonary hypertension (PH) is defined

haemodynamically as a mean pulmonary arterial pressure of>25 mmHg atrest or 30 mmHg with exercise.2 PAH is specifically diagnosed by excluding

other causes of PH, particularly left heart disease. Historically, much atten-

tion focussed on idiopathic and familial PAH (formerly known as primary

PAH).14 However, the contemporary view of PAH now recognizes a broader

variety of aetiologies and associated conditions that may be targeted by

PAH-specific therapies.1

This broadened view of PAH has highlighted a number of clinical quandariesin relation to its detection, diagnosis, and management. It has also stimulated

the development and application of more effective treatment strategies to

limit morbidity, improve quality of life, and prolong survival.

1

1Introduction


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It is clear that responsibility for attaining the best possible health outcomes in

this group of patients lies beyond experts in the disease (who have tradition-

ally resided in Centres of Excellence in PAH) and extends to clinicians of all

specialities and health professions who see many difficult and unusual cases

in their clinical practice.

Aims of this bookThis clinicians guide to PAH is designed to address several aims (Box 1.1).

Box 1.1 Aims of this clinicians guide to PAH

Enhance the overall PAH awareness of the wider clinical community.

Facilitate an understanding of the epidemiology, pathophysiology, and

clinical profile of PAH.

Emphasize the need for active screening of high-risk patients and outline

the screening and diagnostic process of identifying PAH.

Outline the range and effectiveness of treatment options once PAH has

been definitively diagnosed.

Encourage the utilization of Centres of PAH Excellence.

Promote a more collaborative and proactive model of health care to

improve PAH-related health outcomes.

Additional PAH resourcesThis clinicians guide to PAH does not contain definitive and exhaustive

information concerning PAH. Instead, it attempts to encapsulate the most

important aspects of its detection and management. To assist those clinicians

in search of more definitive information, an Appendix lists some of the most

useful websites relating to PAH. Each chapter cites the most relevant and

contemporary references, which are listed at the back of the book.

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Definition of pulmonary arterial hypertensionIn normal circumstances, resting pulmonary artery systolic pressure ranges from

18 to 25 mmHg (mean pulmonary artery pressures 1216 mmHg). Pulmonarycirculation, therefore, usually operates within a low resistanceenvironment and

any increase in pulmonary vascular resistance leads to pulmonary hypertension.

Pulmonary arterial hypertension is defined as a mean pulmonary artery pressure

>25 mmHg at rest or >30 mmHg with exercise. The severity of PAH can be fur-

ther delineated on the basis of this pressure (Box 2.1).

Box 2.1 Severity of PAH

Mild: 2545 mmHg

Moderate: 4665 mmHg

Severe: >65 mmHg

There are many potential causes of PAH and it therefore represents a hetero-

geneous clinical phenomenon that requires further elucidation to ensure

appropriate screening, diagnosis, and management (Figure 2.1).1618

Diagnostic classification

In order to facilitate the detection, diagnosis, and treatment of the many formsof pulmonary hypertension, including PAH, the WHO sponsored an expert

consensus conference in Evian, in 1998 where a formal classification system

was formulated. This system was recently updated and published following

an expert meeting in Venice, in 2003.1

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2Disease background andepidemiology of pulmonaryarterial hypertension


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Table 2.1 shows the current classification system used to categorize the vari-

ous forms of PH and the specific subcategory of PAH. It is important to note

that modifications in the nomenclature relating to PAH involved the replace-

ment of the term primary pulmonary hypertension (PPH) in favour of idio-pathic PAH, and the recognition of familial PAH as a separate category. In

addition, PAH is recognized as being related to rather than secondary to

coexisting diseases such as connective tissue disease, HIV infection, and por-

tal hypertension. Changes to other categories of pulmonary hypertension

clarify terminology rather than rearrange the whole classification system

devised by the WHO working group in 1998.

EpidemiologyGiven the inherent difficulty in detecting and providing a definitive diagnosis

of PAH, it should come as no surprise that its true incidence and prevalence

within the general population is unknown. Most data emanate from national

6

Figure 2.1 Chest radiography suggestive of underlying PAH.The chest X-ray of affected

individuals may show prominence of the main pulmonary artery, cardiomegaly, enlarged hilar

vessels, and diminished peripheral vessels due to chronically increased pulmonary pressure.

NB.Although up to 85% of patients with PAH develop an abnormal chest X-ray or12-lead electrocardiograph (ECG), definitive assessment of pulmonary pressure is required

for diagnosis of PAH (see Chapter 4).16


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Table 2.1 Clinical classifications of pulmonary hypertension1

1. Pulmonary arterial hypertension (PAH)

Idiopathic PAH

Familial PAH

Related to:

Connective tissues diseases

HIV

Drugs and toxins

Portal hypertension

Anorexigens

Congenital heart disease (systemic to pulmonary

shunts, e.g. Eisenmengers syndrome)

Persistent pulmonary hypertension of the newborn

Significant venous and/or capillary involvement

2. Pulmonary hypertension with left heart disease

Left-sided atrial or ventricular heart disease

Left valvular disease

3. Pulmonary hypertension with lung disease and/or hypoxaemia

Chronic obstructive pulmonary disease

Interstitial lung disease

Sleep disorder breathing

Alveolar hyperventilation disorders

Chronic exposure to high altitude Developmental abnormalities

4. Pulmonary hypertension due to chronic thrombotic and/or

embolic disease

Thromboembolic obstruction of the proximal pulmonary arteries

Thromboembolic obstruction of the distal pulmonary arteries

Non-thrombotic pulmonary embolism (e.g. tumour or parasitic)5. Miscellaneous disorders affecting the pulmonary

vasculature (e.g. sarcoidosis)


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registries and clinical trials and patients most likely to gravitate towards

specialist centres. It is highly unlikely that large-scale population studies will

determine the true epidemiological profile of PAH and those patients lucky

enough to reach a specialist centre may be the exception rather than the rule.

When considering, for example, heart failure, specialist centres typically treat

younger patients in whom a differential diagnosis is less clouded by concur-

rent disease states and there are more severe symptoms due to advanced pro-

gression of the underlying disease state. There is little reason to presume that

PAH differs from the heart failure scenario, except that in PAH there is a pre-

ponderance of younger women as opposed to younger men.9,10

This does not invalidate the type of epidemiological data published to date; it

merely emphasizes the need for clinicians to resist stereotyping patients and

ignoring clinical indications that a middle-aged man, for example, has devel-

oped right heart failure secondary to undiagnosed idiopathic PAH.

IncidenceIdiopathic and familial PAH have been reported to generate 12 cases per

million each year in the USA.5 Other causes of PAH, most notably collagen

vascular disease (e.g. systemic sclerosis)

7,8

and congenital abnormalities lead-ing to systemic to pulmonary shunts (e.g. Eisenmengers syndrome)12,1921 are

reported to be associated with a similar incidence rate. Contemporary data

from the National Registry of PAH Centres of Excellence in France are con-

sistent with these early reports.9

However, recent data from the whole Scottish population (with supportive data

from a PAH Centre of Excellence) suggest that the incidence of idiopathic/

familial PAH over the 16-year period 19862001 was 4 cases per million/annum (3 and 4 cases per million/annum in men and women, respectively) in

those aged 1665 years.15 The equivalent rates for PAH-associated connective

tissue disorders and congenital abnormalities during this period ranged from

1 to 3.5 cases per million/annum, respectively, in that country. Although these

data showed that incidence rates have remained fairly constant in this age

group, they also show that an increasing number of older individuals (aged

>65 years) are being diagnosed with PAH. Consistent with these data, con-

temporary reports from Australia3 suggest that idiopathic PAH generatesapproximately 310 cases per million each year. Certainly, with an increased

awareness of PAH and increased detection rates, the reported incidence of

PAH has risen in the past decade.

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PrevalenceThere are very few reports of the prevalence of PAH. However, given the rise

in reported incident cases and improved survival rates, most probably due tothe introduction of relatively effective treatment strategies (see Chapter 5), the

underlying prevalence is most likely rising. In Scotland (total population

5 million), for example, the total number of surviving men and women aged

65 years or less being actively treated for idiopathic PAH, PAH related to scle-

roderma, and PAH related to congenital heart disease is reported to be 25, 15,

and 12 cases per million per population.15 The total point prevalence of these

forms of PAH in Scotland in 2002 was 52 adult patients per million. Two-

thirds of these cases are women and these estimates were confined to those

aged < 65 years. Once again, these are likely to be underestimates of the true

prevalence of PAH given that detected numbers of patients do not reflect the

likely contribution of conditions such as connective tissue disorders.

9

0

10

20

30

40

50

60

70

80

90

One-year rate

Connective PAH

Congenital PAH

Idiopathic PAH

Connective PAH

Congenital PAH

Idiopathic PAH

Five-year rate

All-causemortality(%)

Figure 2.2 Actuarial 1- and 5-year case-fatality rates (men in red and women in yellow)

related to PAH derived from Scottish population data (19862001). Figure adapted fromoriginal data.10


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Prognostic implicationsWithout treatment, the prognosis for patients with significant PAH is poor.

Historically, the reported median life expectancy of those with idiopathic

PAH in the era prior to PAH-specific treatments (see Chapter 5) was 2.8 years

from diagnosis.5

Similarly, 2-year survival rates in PAH associated with col-lagen vascular disease were reported to be as low as 4055%6 and PAH is a

leading cause of death in individuals with PAH complicating systemic sclero-

sis.7,8 Contemporary reports from France9 and Scotland10 have underlined the

potential prognostic impact of a new era in PAH-specific management.

Recent whole population data from Scotland for the period 19862001

demonstrate that in the pre PAH-specific treatment era, mortality rates related

to all forms of PAH were extremely high. For example, Figure 2.2 shows the1- and 5-year actuarial survival rates associated with idiopathic, connective

tissue, and congenital heart disease related PAH in hospitalized patients aged

1665 years during this period.15

These data are derived from the linked Scottish Morbidity Record Scheme.22

Largely consistent with data from the National Institute of Health in the

USA, 1-year case fatality in those with PAH associated with collagen vascu-

lar disease was 25%, rising to 70% at 5 years. A comparison of the demo-graphic profile of incident cases highlighted the fact that patients with

connective tissue disorders are more likely to be screened for PAH and

treated earlier. It should be noted, however, that patients with connective

tissue-related PAH commonly have a worse prognosis than those with idio-

pathic PAH when presenting with the same haemodynamic profile.

A major limitation of population-derived data is the lack of specific detail

collected concerning the progression of disease. As Figure 2.3 demonstrates,patients who exhibit more advanced symptomology, as determined by a more

severe WHO classification (Class IV compared with Class II and III), have a

markedly worse prognosis.5 Overall, these data reinforce three important

points in relation to PAH:

regardless of extent of disease progression and associated disease states,

survival rates in PAH are poor the potential for positive effects of new modalities of treatment is high there is a strong possibility that earlier detection and proactive management

of PAH will slow the typical disease progression/deterioration.23

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11

0

0Days of follow-up

300 600 900 1200 1500

20

10

40

30

60

50

80

70

90

Cumulativemortality(%)

WHO Class IV

WHO Class II and III

Figure 2.3 Differential sur vival based on WHO Classification of PAH-related symptoms

(Class II & III vs Class IV). Figure adapted from original data.5

0

10

20

30

40

50

60

19861989 19901993 19941997

One-yearcasefatality(%)

Idiopathic PAH

Connective PAH

19982001

Figure 2.4 Trends in 1-year actuarial survival in patients with idiopathic PAH or PAH

related to a connective tissue disorder. Figure adapted from original data.10


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In support of the above clinical points and the importance of functional class

and survival, Williams and colleagues demonstrated functional improvements

and halving in the relative risk of dying associated with PAH-specific treat-

ments in a cohort of patients with PAH related to connective tissue disor-

ders.23 Figure 2.4 shows historical improvements in the survival of the same

type of hospitalized patients (aged 1665 years) in Scotland.10

When combined with low PAH-related mortality rates recently reported from

France,9 these data emphasize the potential to dramatically improve survival

rates via early detection and intervention with PAH-specific treatments.

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Introduction to the pathophysiology of PAHOur understanding of the pathophysiology of PAH is still in its infancy,although significant advances have been made based on molecular science,

genetics, and the understanding of the clinico-pathological interactions rec-

ognized in the WHO classification scheme. Undoubtedly, the pathophysiol-

ogy of PAH is complex, pivoting around the concepts of vasoconstriction,

vascular remodelling, and thrombosis. Vasoactive substances, growth factors,

inflammatory mediators, and components of the clotting/coagulation system

are all involved to varying degrees.24

This complex interplay is only justbeing decoded, but already there have been both real and potential therapeu-

tic targets unearthed.

This chapter will discuss some of the underlying mechanisms and mediators

responsible for (or associated with) the development of PAH, and how these

interact to cause the problems encountered in clinical practice.

Vascular wall remodelling/vasconstrictionand platelet activation

Mechanisms

Postmortem studies of PAH typically show histopathological changes in pul-

monary resistance arteries, characterized by marked obstructive lesions.2527

These lesions represent proliferation of endothelial and smooth muscle cells

and are the hallmark of PAH.28 They cause progressive occlusion of the

vessel lumen and provide an obvious reason for the development of PAH (see

Figure 3.1). These lesions also highlight the fact that definitive treatments for

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3Pulmonary arterialhypertension increasingour understanding ofdisease pathophysiology


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14

Normal

Vasoconstriction

Plexiforml

esion

Adventitia

Media

Intima

Earlyintimal

proliferation

Medial(smooth

muscle)hypertrophy

Medial(smooth

muscle)hypertrophy

Le

sion

Th

rombosisV

ascular

proliferation

Figure

3.1

De

velopingobstructiveplexif

orml

esionsinpulmonary

arteries.


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PAH will require agents with antiproliferative and/or remodelling potential, as

opposed to pure vasodilator treatments.29,30 Reinforcing the importance of

these lesions and potential therapeutic strategies, this process has been

recently described as tumour-like in its development.30 PAH can, however,

develop in the absence of these distinct lesions in the pulmonary vasculature.

In this setting, it is likely there are diffuse changes in the structure of pul-

monary resistance arteries, in addition to altered vasoreactivity (provoking

vasoconstriction) and increased platelet activation (leading to thromboem-

bolism) leading to progressive PAH.31,32

Figure 3.2 represents an algorithm demonstrating how all three key compo-

nents of PAH (vasoconstriction, vascular wall remodelling, and platelet

activation/aggregation) have the potential to form a pathological triad that

may lead to a cascade of vascular dysfunction, increasing pulmonary vascu-

lar resistance and progressive clinical deterioration. Standard pharmacolog-

ical treatment of PAH (see Chapter 5) aims to interrupt this pathological

cascade.

15

Keys: nitric oxide,

prostacyclins

and endothelin

Keys: serotonin,

tumour growth

factors, and K+

channel function

Hypoxaemia/thromboembolism/

endothelial dysfunction

PROGRESSIVE PAH

Platelet

activationSmooth cell

proliferation

Endothelial

dysfunction

Pulmonary vascular dysfunction/occlusion/thromboembolism

Genetic predispositionPre-existing risk factor

Pulmonary vascularinsult

Figure 3.2 Algorithm of the pathophysiology of PAH.


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Vasoreactivity

Normal resting (pulmonary) arterial tone is maintained by a balance of endoge-

nous vasodilators and vasoconstrictors. Studies of PAH have shown that an

imbalance on either side can lead to the development of pulmonary hypertension.

In addition, many of these endogenous substances not only affect resting vascu-lar tone (vasoconstriction or dilatation) but also have effects on cell (especially

smooth muscle) proliferation, platelet aggregation, and vascular remodelling.

For example, levels of nitric oxide (NO) and prostacyclin are diminished in

PAH.28,29,3335 Nitric oxide and prostacyclin are both potent endogenous vasodila-

tors. Prostacyclin also has potent antiplatelet effects and inhibits smooth muscle

cell proliferation. Both these agents have proven to be effective treatments for

PAH see Chapter 5.34,36 Conversely, vasoconstrictors such as endothelin and

thromboxane are present in increased concentrations in pulmonary hyperten-sion. Endothelin, in particular, has potent proliferative effects. Thus, endothelin

provides an attractive target for effective therapy in PAH.35,3743

Endothelin

Endothelin is a potent and long-lasting vasoconstrictor that is 100 times

more potent than noradrenaline (norepinephrine).38 In addition to being a

potent vasoconstrictor, it is directly associated with fibrosis (predominantlymediated via the ETB receptor), vascular cell hypertrophy, inflammation, and

neurohormonal activation.44,45 Its synthesis is triggered by numerous factors,

including localized mediators such as inflammatory cytokines, and extrinsic

factors such as low oxygen tension and increased arterial wall shear stress

(e.g. in the presence of an obstructive plexiform lesion in the pulmonary

vasculature).45,46 The elevation of both plasma and tissue endothelin levels,

and increased expression of endothelin receptors, are seen in pathologicalconditions such as PAH, acute and chronic heart failure, cardiogenic shock,

acute coronary syndromes, and fibrotic lung disease.47 Its role in connective

tissue diseases is well documented, with evidence suggesting that elevated

endothelin levels contribute to the vascular and fibrotic manifestations char-

acteristic of systemic sclerosis.48

High plasma endothelin levels have been shown to correlate not only with

severity of disease but also with prognosis for patients with both idiopathicPAH and that relating to connective tissue disease.42,43 The growing evidence

of the pathological role of endothelin in PAH has led to the development of

endothelin receptor antagonists, such as bosentan, sitaxsentan, and ambrisen-

tan, as a targeted therapeutic approach to disease pathogenesis.35,49,50

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K+ channel function

Abnormal K+ channel function in pulmonary vascular smooth muscle also

appears to be involved in the development of PAH. Hypoxia has been shown

to selectively inhibit the function and expression of voltage-gated K+ channels

in pulmonary arterial smooth muscle cells. Via this mechanism, acute hypoxiainduces membrane depolarization, and a rise in cytosolic Ca2+ that triggers

vasoconstriction. In addition, caspace activity is inhibited, resulting in an inhi-

bition of apoptosis, and unchecked cell proliferation resulting in vascular

remodelling.5153

In addition to the above, it is useful to consider the way pulmonary hyperten-

sion is now classified to give us insights into the underlying pathophysiology.

In part, this classification was born from an understanding of the differentcontributions of various disease states to the development of pulmonary

hypertension, and PAH in particular.

The genetic basis of PAHIn the original (1998) WHO classification, familial PAH was thought of as a

subsection of so-called primary pulmonary hypertension.1 The latest classifi-

cation, however, recognizing the identification and clarification of the generesponsible for familial PAH, classifies this as a separate entity.10 Furthermore,

it is known that the genetic defect(s) responsible for familial PAH is present in

10% of cases of idiopathic PAH.4

The gene defects identified as the cause of familial PAH are related to muta-

tions in the bone morphogenetic protein receptor type 2 (BMPR2). This

receptor and its ligand (bone morphogenetic protein 2) are part of the trans-

forming growth factor beta (TGF-) superfamily of signalling pathways.Normal activation of this receptor produces signals that inhibit proliferation,

particularly of pulmonary artery smooth muscle cells. More than 40 BMPR2

gene mutations have been identified, and all lead to loss of this inhibition of

cellular proliferation.5456

In addition to the BMPR2 abnormalities, mutations in other genes have also

been proposed as having a role in the development of pulmonary hyperten-

sion. Mutations in the ALK-1 receptor (activin-like kinase), also a member ofthe TGF- family, have been linked to the development of PAH in patientssuffering from hereditary haemorrhagic telangiectasia.57 Likewise, genetic

polymorphisms of the serotonin transporter (5-HTT) have been linked with

PAH associated with hypoxia and fenfluramine use.58 The role of these and

17


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other genetic abnormalities is providing a very fruitful area of research into

both the pathogenic mechanisms underlying the development of PAH and the

identification of potential therapeutic targets.

Systemic sclerosis (scleroderma)Pulmonary hypertension is recognized as a lethal complication of all forms ofsystemic sclerosis. Endothelin has been postulated as having a pivotal role in

the pathogenesis of the pulmonary vascular disease associated with this con-

dition, which has all the hallmarks pathologically of PAH.7,8,48 There are,

however, significant clinical differences compared to other forms of PAH,

relating principally to late presentation and/or recognition of the pulmonary

vascular abnormality. This occurs in the main because of the significantco-morbidities associated with the underlying condition that often dominate

the clinical presentation early in the disease. As a consequence, patients with

systemic sclerosis often present in advanced stages of right ventricular dys-

function and functional decline, and, as a result, treatment outcomes are gen-

erally less satisfactory when compared to idiopathic PAH for example:

although there is evidence that survival rates are improving in this group with

the application of more specific PAH treatments.10,23

Pulmonary hypertension remains the most common cause of mortality in sys-

temic sclerosis. Any patient with systemic sclerosis may present at any stage

in their disease with vasculopathy, interstitial lung disease, or a combination

of both.59

Other causes of PAH

As indicated in Table 2.1, portal hypertension,14

human immunodeficiencyvirus (HIV) infection,13,60 and anorectic agents11,58 are external factors that

can also lead to PAH. The use of appetite-suppressant drugs (amphetamine

derivatives such as fenfluramine and dexfenfluramine) for more than 3

months is associated with a greater than 30-fold increased risk of developing

pulmonary hypertension.58 This complication has been linked to abnormal

serotonin metabolism and polymorphisms in the serotonin transporter mecha-

nism. The precise mechanisms by which portal hypertension and HIV infec-

tion lead to PAH are unknown.

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Congenital abnormalitiesPulmonary vascular remodelling occurs in response to the shear stress caused

by significant increases in pulmonary blood flow. This situation is most com-

monly encountered in congenital heart disease associated with systemic to pul-

monary shunts.20,21,61

The chronic increase in pulmonary blood flow leads to thedevelopment of PAH that is pathologically indistinguishable from idiopathic

PAH. When the pulmonary arterial pressure exceeds systemic levels, reversal

of the shunt occurs, with resultant cyanosis Eisenmengers syndrome.19

Persistent pulmonary hypertension of the newborn (PPHN) is a rare disorder

of neonates. An elevated pulmonary vascular resistance is required for an

effective fetal circulation; however, if this state persists after birth, pulmonary

to systemic shunting occurs through persisting fetal channels (e.g. the ductusarteriosus), thereby bypassing the lungs and resulting in systemic arterial

hypoxaemia.20,33 As in many forms of PAH, the mechanisms underlying the

development of pulmonary hypertension in this setting are poorly under-

stood. The outcome of this condition, however, has been markedly improved

with the use of inhaled nitric oxide therapy.

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Clinical profileIt is important to remember that the key underlying haemodynamic factor in

any form of PH is the increase in the pulmonary vascular resistance inresponse to the remodelled pulmonary circulation. The primary driver of this

pathological process, therefore, is largely clinically silent until the response is

manifested by changes (both acute and chronic) in right ventricular function.

As such, without treatment, to relieve chronic PAH, particularly in its severest

form, patients typically develop progressive right ventricular hypertrophy,

dilatation, and associated right ventricular dysfunction see Figure 4.1.6265

Without appropriate treatment, therefore, the right ventricle progressivelyfails, eventually resulting in death.

As indicated, many of the pathological changes associated with PAH may

not produce significant and readily indentifiable symptoms until the disease

has progressed significantly (i.e. when right heart failure has developed as a

consequence of increased pulmonary vascular resistance). In addition, the

clinical profile of PAH may also be obscured by the underlying disease state

(e.g. systemic sclerosis), particularly where other factors have a detrimentaleffect on exercise tolerance.

Symptoms

The most common symptom of PAH is progressive exertional dyspnoea.

Overall, a patients description of the presenting symptoms is often vague

and may lead to an alternative diagnosis (e.g. asthma). Depending on the

stage of disease and degree of right ventricular compromise, patients can

also present with symptoms such as:

21

4Pulmonary arterialhypertension clinical profileand diagnosis


31/72

presyncope and syncope central chest pain

fatigue

palpitations

cough and occasionally haemoptysis.

Signs

Physical examination is often normal in early stages of the disease process,with the classical signs of pulmonary hypertension only becoming evident as

right ventricular hypertrophy and failure develop. The following signs are

indicative of right ventricular hypertrophy or pre-established right heart fail-

ure secondary to chronic PAH:

left parasternal systolic lift accentuated pulmonary valve closure sound (loud P2)

tricuspid regurgitant murmur raised jugular venous pressure

RV 3rd heart sound

hepatomegaly

peripheral oedema and ascites.

22

Figure 4.1 Right ventricular failure secondary to pulmonary arterial hypertension.

PAHresistant and cardiac

workload

RV dilatation

RV hypertrophy


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Clinical investigations

Diagnostic investigations are shown in Box 4.1.66

Box 4.1 Clinical investigations of PAH

Imaging:

chest radiograph

echocardiogram

ventilation perfusion scan

high-resolution computed tomography (CT) of the lungs.

Respiratory:

arterial blood gases in room air

lung function testing

nocturnal oxygen saturation monitoring.

Cardiology:

electrocardiography (ECG)

six-minute walk test (6MWT)

right heart catheterization.

Blood investigations:

biochemistry and haematology

thrombophilia screen human immunodeficiency virus (HIV).

Urine:

-hCG (beta-human chorionic gonadotrophin) women.

Routine investigations will provide evidence suggesting the diagnosis of pul-monary hypertension. For example, Figure 4.2 shows the pattern of right ven-

tricular strain seen in the ECG of a patient with right ventricular

hypertrophy secondary to PAH. The majority of patients with PAH have an

abnormal ECG.1 Similarly, a chest X-ray may show proximal pulmonary

23


33/72

artery enlargement and/or cardiomegaly. Both 12-lead ECG and chest X-ray

represent readily available screening tools for PAH (see Chapter 6), but it

must be emphasized that both tests may be substantially normal in patients

with symptomatic PAH, particularly in the earlier stages of the disease, but

also occasionally in later disease stages.66

If pulmonary hypertension is suspected clinically, the next step is to evaluate

the patient with transthoracic echocardiography. Doppler assessment of theright ventricular systolic pressure (RVSP), through measurement of the tri-

cuspid regurgitant jet, gives an estimate of pulmonary artery pressure.

In addition, there may be evidence of right ventricular hypertrophy and

dysfunction.6770

There is emerging evidence that stress echocardiography may be an appro-

priate strategy for case-finding patients at high risk of developing PAH

(i.e. those with a connective tissue disorder).70

To confirm the diagnosis of PAH, raised left atrial pressure must be excluded

by right heart catheter.66 This procedure allows accurate measurement of

pulmonary haemodynamics and determination of the patients prognostic

24

I aVR VI V4

II aV1 V2 V5

III aVF V3 V6

Figure 4.2 12-lead ECG from a patient with right ventricular failure/hypertrophy

secondary to PAH. Note the typical right ventricular strain pattern and right axis

deviation, as denoted by positive R waves in leads V1,V2, and aVI.


34/72

outlook.65 Investigations used to either rule out PH or confirm associated

pathology (e.g. pulmonary embolism) are further described in Chapter 6.

Clinical indicators of disease progression

There are a range of non-invasive and invasive indices/parameters used tomonitor disease progression in PAH. The most commonly used of these are

described below.

WHO functional class

As worsening dyspnoea on exertion is the most obvious and probably most

sensitive marker of the underlying disease progression associated with PAH,

it has proven to be the most practical means of delineating the clinical statusof affected patients. As such, the WHO adopted the NYHA functional class

(first applied to heart failure)71 to stratify the clinical status of patients with

PAH, and guide appropriate management according to their response/

non-response to medical treatment (Table 4.1).

Patients whose clinical profile is consistent with WHO Class IV usually have

signs of advanced right heart failure and there is little doubt that the progres-

sion from WHO Class I to IV mirrors the evolution/progression of right-sidedheart failure secondary to the underlying PAH. As can be appreciated,

patients in WHO Class I with underlying PAH are unlikely to be diagnosed

unless investigated for another reason. Most patients present in WHO Class

III and IV and have already developed right ventricular dysfunction.

Six-minute walk test

In addition to asking patients about their physical limitations and classifyingtheir responses according to an agreed formula (e.g. WHO class), it is clearly

desirable to gain a more objective measure of their functional capabilities. In

this respect, the easiest, most tolerated and realistic test of a patients ability

to carry out activities of daily living is the 6-minute walk test (6MWT). This

test is as simple as it sounds, only requiring an experienced supervisor to

measure how far a patient can walk over a flat and unobstructed surface

(32 metres in length) during the predefined time-frame of 6 minutes.72,73 This

simple walk test is sensitive to changes in cardiac function and can predict

subsequent morbidity and mortality in PAH patients.74 Like the WHO class,

the results of this walk test may vary, so it is important to examine historical

trends in patients rather than rely on a single test (i.e. using the patient as

25


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36/72

Clinical Excellence, are pivotal to determining a specific cause and diagnosis

of PAH, with associated decisions relating to appropriate treatment and prog-

nostic outlook:

pulmonary artery pressure

cardiac index

pulmonary vascular resistance

right atrial pressure

pulmonary capillary wedge pressures.

It is important to note, of course, that the definitive diagnostic tool for PAH

is right heart catheterization, providing a direct measure of pulmonary

pressures.66

Respiratory function tests

These tests may include lung volumes and carbon monoxide (CO) diffusion

capacity. Respiratory function tests often show a disproportionate reduction

in carbon monoxide diffusion in the lung (DLCO around 50% of predicted

in moderate PAH), with at most a mild-to-moderate restrictive lung defect.

The reduction in DLCO is greater than that seen with comparable sympto-matic left heart failure and reflects the loss of effective or functioning pul-

monary vasculature characteristic of PAH.66 Pulmonary diffusing capacity

may be clinically important in uncovering PAH in high-risk patient groups

(e.g. those with connective tissue disorders).59

27


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The evolving treatment of PAHTo the uninitiated it may appear that there has always been a wealth of PAH-

specific therapies available. However, it has only been in recent years that

the therapeutic armoury to effectively manage PAH has dramatically

increased; hence, historically poor survival rates. It was not until 1981 when

heartlung transplantation was introduced, that an effective treatment for

PAH became available. Challenged by the limited number of organ donors,medical treatments have been sought, the most successful of which can now

postpone the need for transplantation.

Increasing interest in PAH has led to many advances in treatment. The 3rd

World Symposium on Pulmonary Arterial Hypertension (Venice 2003) repre-

sented a significant event in the clinical management of PAH. At this time,

an expert task force was able to review clinical trial data to determine the

clinical efficacy of a broad range of therapeutic strategies. A published reportarising from this meeting76 and subsequent expert guidelines published in

Europe and North America,1618 now provide clinicians with a strong evi-

dence base to manage patients with PAH.

Figure 5.1 synthesizes the latest expert advice published following the 2003

World Symposium76 and the most recent North American guidelines.18 In both

cases, a grading system, based on the strength of clinical trial evidence for

study design and efficacy, was applied to each treatment listed in this figure.Epoprostenol77,78 bosentan,79 inhaled iloprost,80 and sildenafil81 were all

awarded the highest strengths of expert recommendation.18,76 Importantly, in a

rapidly evolving therapeutic environment the choice of first-line therapy for

patients with symptomatic PAH now involves a combination of prostacyclin

29

5Improving outcomes inpulmonary arterialhypertension pharmacologicaland surgical treatmentstrategies


39/72

30

analogues, endothelin receptor antagonists, and phosphodiesterase type 5

inhibitors. In this context, choice of therapy takes into consideration, evidence,clinical judgement, regulatory approval, mode of administration, adverse event

profile, cost, and patient preferences. The role and purpose of these treatments

are overviewed, tabulated, and presented in more detail in Table 5.1.

Yes

Yes No

No

VASOREACTIVE?

Endothelin receptor antagonist

(bosentan, sitaxsentan, ambrisentan)

Prostanoid analogue

(iloprost/treprostenol/epoprostenol)

Phosphoidesterase V inhibitor

(sildena fil)

Prostanoid analogue

(IV iloprost/treprostinil/eporostenol)

Endothelin receptor antagonist

(bosentan)

Atrialseptostomy Lung transplant

or

Combination Pharmacotherapy

Maintain therapy

Refractory to treatment

NYHA Class II or III

NYHA Class IV

Pulmonary Arterial Hypertension

NYHA Functional Class II/III/IV

Conventional therapy

Oxygen support diuretic therapy

Sustained response

to CCB?

Figure 5.1 A synthesis of current evidence-based guidelines for the management of

pulmonary arterial hypertension.18,76 CCB = calcium channel blocker, IV= intravenous.


40/72

31

Treatment

Anticoagulation:

warfarin

Oxygentherapy

Supportivem

edical

therapy:diuretics,

digoxin

Calciumantagonists:

diltiazem,nife

dipine,

amlodipine

Indication

Preventiono

fpulmonary

arterialt

hrombosis

Patientwitha

ssociatedlung

disease.Adultnocturnal

desaturation(2L/min)

Presenceofrightheart

failure.D

igox

inmay

improvecard

iacoutputin

refractorypa

tients

Reductionin

pulmonary

arterypressure(PAP).

Reductionin

mortality

withsustaine

dresponse.

Patientswith

right

ventricularim

pairment

shouldbeco

nsideredfor

Contraindications

Cautio

ninconnective

tissuedisease

Maycausesome

vasoconstriction.Usewith

caution

andcloselymonitor

Digoxinusedwithcaution

intheelderlydueto

potent

ialtoxicity

Calciumantagonists

should

notbestarted

before

anacutevasodilator

study.Patientswhodo

notrespondtoa

vasodilatorchallenge

would

beunlikelyto

C

omments

A

ssociatedwithprolongedsurvivalin

idiopathicPAH.63

Therea

reno

p

ublisheddatainotherfo

rms

o

fPAH

Integralpartofthemanagementofall

formsofpulmonaryhyper

tension1,1

241

27

D

iureticsremainthegoldstandardfor

symptomreliefoffluidove

rloadinright

h

eartfailure.12

8ACEinhibitorsand

b

eta-blockersaresuperior

todigoxinin

o

therformsofheartfailure129

A

patientdemonstratinganacute

responsetoavasodilator

testis

d

efinedasareductioninmPAPbyat

least10mmHgtoatleast

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Clinician's Guide to Pulmonary Arterial Hypertension - Pocketbook

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